FcγRIIa Ligation Induces Platelet Hypersensitivity to Thrombotic Stimuli
FcγRIIa Ligation Induces Platelet Hypersensitivity to Thrombotic Stimuli
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DOI：
10.1016/j.ajpath.2012.09.005
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发表时间：
2013-01-01
影响因子：
6
通讯作者：
Worth, Randall G.
中科院分区：
文献类型：
--
作者：
Berlacher, Mark D.;Vieth, Joshua A.;Worth, Randall G.
血小板以其在止血中的重要作用而闻名，然而其在其他功能（包括炎症和感染）中的重要性正变得越来越明显。已知系统性红斑狼疮（SLE）患者的血液中具有循环IgG复合物，并且对血栓形成事件高度敏感。由于血小板表达IgG的单一受体，我们检验了该受体（Fc γ RIIa）的连接诱导血小板对血栓形成刺激物超敏反应的假设。SLE患者的血小板对凝血酶的敏感性显著高于健康志愿者，这与SLE血小板表面IgG水平升高相关。为了测试Fc γ RIIa连接是否刺激凝血酶超敏反应，将来自健康志愿者的血小板与缓冲液或热聚集的IgG孵育，然后用增加浓度的凝血酶刺激。有趣的是，热聚集的IgG刺激的血小板，而不是缓冲液处理的血小板，对凝血酶过敏，超敏反应被阻断的抗Fc γ RIIa单克隆抗体（mAb）。凝血酶超敏反应不是由于凝血酶受体表达（GPIb α或PAR 1）的变化，而是依赖于共享信号分子的激活。这些观察结果表明，IgG复合物对血小板Fc γ RIIa的连接诱导过敏状态，由此血栓形成刺激的微小变化可能导致血小板活化和随后的血管并发症，如短暂性脑缺血发作或中风。(Am J Pathol 2013，182：244-254; http：//dx·doi·org/10·1016/j·ajpath·2012·09·005）
Platelets are known for their important role in hemostasis, however their significance in other functions, including inflammation and infection, are becoming more apparent. Patients with systemic lupus erythematosus (SLE) are known to have circulating IgG complexes in their blood and are highly susceptible to thrombotic events. Because platelets express a single receptor for IgG, we tested the hypothesis that Ligation of this receptor (Fc gamma RIIa) induces platelet hypersensitivity to thrombotic stimuli. Platelets from SLE patients were considerably more sensitive to thrombin compared to healthy volunteers, and this correlated with elevated levels of surface IgG on SLE platelets. To test whether Fc gamma RIIa ligation stimulated thrombin hypersensitivity, platelets from healthy volunteers were incubated with buffer or heat-aggregated IgG, then stimulated with increasing concentrations of thrombin. Interestingly, heat-aggregated IgG stimulated platelets, but not buffer-treated platelets, were hypersensitive to thrombin, and hypersensitivity was blocked by an anti-Fc gamma RIIa monoclonal antibody (mAb). Thrombin hypersensitivity was not due to changes in thrombin receptor expression (GPIb alpha or PAR1) but is dependent on activation of shared signaling molecules. These observations suggest that ligation of platelet Fc gamma RIIa by IgG complexes induces a hypersensitive state whereby small changes in thrombotic stimuli may result in platelet activation and subsequent vascular complications such as transient ischemic attacks or stroke. (Am J Pathol 2013, 182: 244-254; http://dx.doi.org/10.1016/j.ajpath.2012.09.005)